Two monoclonal antibodies directed against PCSK9 have been evaluated in CV outcome trials; evolocumab in the FOURIER trial1 and alirocumab in the ODYSSEY OUTCOMES trial.2 Different patient populations were studied in these trials; the FOURIER trial primarily enrolled patients with a history of myocardial infarction (MI), with peripheral arterial disease (PAD) and a history of stroke, whereas the ODYSSEY OUTCOMES trial focuses on patients with a recent MI (< 1 year). The FOURIER trial showed a decrease of 15% in the composite endpoint (CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) and CV benefit across all patients subgroups.3 One of the key features of this trial was the addition of evolocumab on top of intensive statin therapy compared to placebo, standard care and statin therapy. Moreover, this trial was the first that attained an on-treatment LDL-c level less than the ESC target of 70 mg/dL in secondary prevention patients; the target level attained had a median of 30 mg/dL (0.75 mmol/L).

Foam cells play a key role in the development of plaques and plaque vulnerability by driving inflammation through their secretory profile.

The FOURIER trial raised the question of the relationship between highly efficacious lowering of LDL-c and event reduction. The missing link here is the pathophysiology of atherosclerotic CVD (ASCVD), in other words the disease process. Thus, more importantly, what is the impact of LDL-c lowering on this missing link? By focusing on the pathophysiology of atherosclerosis, we can perhaps better understand the impact of the very low levels of LDL-c obtained in the FOURIER trial.

The formation of atherosclerotic plaques in the arterial tree, primarily in the coronary tree, takes place at sites of predilection. Endothelial dysfunction is involved and is a consequence of a number of risk factors. One of them is LDL-c, a major driver of plaque formation. Sites of endothelial dysfunction show enhanced permeability and as a result, LDL-c penetrates the intima more efficiently. This higher influx of LDL-c results in accumulation of cholesterol derived from LDL. LDL undergoes modification, which may involve oxidation. In addition, monocytes adhere and penetrate at sites of plaque predilection, and subsequently transform into macrophages. The uptake of modified LDL in those macrophages of the M1 (proinflammatory) phenotype results in formation of macrophage foam cells, which give rise to the earliest lesions of ASCVD, also called fatty streaks.

Then, intraplaque formation starts as a result of growth factors and proinflammatory cytokines secreted by monocytes/macrophages. These cells also attract regulatory T cells and T helper cells. These T cell subtypes, growth factors and cytokines cause migration of smooth muscle cells from the media into the intima, giving rise to the production of the extracellular matrix (ECM). Interaction between these cells amplifies intraplaque formation.

Foam cells play a key role in the development of plaques and plaque vulnerability by driving inflammation through their secretory profile. More specifically, they drive plaque progression by production of proinflammatory cytokines, an excess of matrix degradation due to the production of matrix metalloproteinases, an excess of oxidative stress due to the production of reactive oxidative species, production of tissue factor (TF) and finally apoptosis and necrosis. The latter two result in formation of the necrotic core in the plaque.

Cholesterol crystals are a feature of mature plaques and they can induce plaque rupture through several mechanisms. Analysis of ruptured plaques showed that these have a marked accumulation of cholesterol, both free cholesterol and cholesterol esters,4 almost exclusively located in macrophage foam cells.5 Focusing on the site of a ruptured plaque shows that the content of the plaque may have come into contact with circulating elements in plasma and blood cells, a major coagulation reaction may be triggered because TF is present, resulting in thrombus formation, either partially or completely occlusive.6

The GLAGOV trial was the first intervention trial with a PCSK9 inhibitor that focused on the potential impact on plaque progression or regression.

Intravascular ultrasound (IVUS) in prevention trials showed that plaque progression can be stopped to a large degree by statin treatment that lowered LDL-c to the critical goal of 70 mg/dL (1.7 mmol/L) In some patients, a small degree of plaque regression is observed, as shown by Nicholls.7 A Japanese study using optical coherence tomography showed plaque volume and lipid content decrease upon lowering of LDL-c by statins, and fibrous volume (the thickness of the fibrous cap) increased. Together, these factors favor plaque stability.8

The GLAGOV trial was the first trial with a PCSK9 inhibitor that focused on the potential impact on plaque progression or regression.9 Evolocumab on a background of optimized statin treatment was compared to placebo on top of statin treatment. IVUS was performed at baseline and 78 weeks.10 Treatment with evolocumab reduced LDL-c to 36.6 mg/dL (60% decrease) and gave a change in total atheroma volume of 6 mm3 compared to 0.9 mm3 in the control group, indicating a significant degree of regression with evolocumab. A significant reduction of 80% in atheroma volume was observed in individuals on evolocumab who had a baseline LDL-c <70 mg/dL.

Several mechanisms in response to highly efficacious LDL-c lowering may contribute to plaque regression and plaque remodeling and ultimately to plaque stabilization and reduction in CV events. Arterial accumulation of LDL-c and apoB-lipoproteins is reduced. Animal studies suggest an efflux of cholesterol and toxic oxidized lipids from the plaque, perhaps mediated by HDL. Marked reduction of intracellular and extracellular lipid content in the plaque has been shown in response to LDL-c lowering, as well as a reduction in plaque inflammation with an increase in ECM, thereby favoring plaque stabilization. Also, animal models have shown an influx of phagocytes, removal of necrotic debris and efferocytosis of macrophages.

Several kinds of evidence support LDL-c as a causal factor in ASCVD, including data from animal models, epidemiology, PCSK9 genetics, trials with statins, cholesterol absorption inhibitors or the first PCSK9 inhibitor. Lowering of LDL-c induces plaque regression, and this results in remodeling of plaque composition and impacts plaque stabilization, thereby reducing CV events. Prof. Chapman concluded by saying that LDL-c is clearly a privileged target and lowering does not only lead to regression and plaque stabilization, but above all reduces CV outcomes.